Organophosphorus (OP) pesticides are among the most heavily used pest control agents worldwide. In the US, malathion and chlorpyrifos account for more than 50% of the millions of pounds of OP pesticides used yearly. An ever growing body of epidemiological studies report that children whose mothers have been exposed to OP pesticides, including chlorpyrifos and malathion, during pregnancy present higher incidence of cognitive impairments, attention deficit/hyperactivity disorder, and autism spectrum disorders than non-exposed children. Although animal studies have confirmed that in-uterus or early postnatal exposure to chlorpyrifos compromises the brain development of rats and mice, the distinct temporal course of brain development and high levels of circulating carboxylesterases (enzymes that inactivate OP compounds) make these rodents inadequate models of human OP toxicity. In addition, even though concerns regarding the toxicity of OPs to the developing brain have been substantiated by their prompt permeation through the placenta, there have been no animal studies addressing the potential developmental toxicity of malathion. The present project is designed to test the central hypothesis that the developmental neurotoxicity of malathion and chlorpyrifos in guinea pigs - the best non-primate model of human OP intoxication - can be counteracted by galantamine and is largely accounted for by epigenetic mechanisms. Galantamine, a drug approved to treat Alzheimer's disease, is known to safely and effectively protect guinea pigs against the acute toxicity of OP compounds [PNAS 103: 13220, 2006]. Galantamine can also prevent the delayed cognitive dysfunctions that result from a single exposure of guinea pigs to sub-toxic doses of OPs. This project uses a multidisciplinary approach that involves electrophysiological, behavioral, magnetic resonance imaging and molecular biological assays to address three specific aims: (i) to identify, at various postnatal ages, neurological, structural, and neurobehavioral correlates of in-uterus exposure of guinea pigs to malathion or chlorpyrifos, (ii) to determine the effectiveness of postnatal treatment with galantamine to counteract the developmental toxicity of those pesticides, and (iii) to examine the contribution of epigenetic mechanisms to the developmental toxicity of the pesticides and the therapeutic effectiveness of galantamine. The overarching goal of this project is to provide fundamental and timely input for assessment and adequate treatment of the human developmental toxicity of malathion and chlorpyrifos. The results of this highly translational study of the potential health risks associated with exposure of the immature brain to pesticides will be far reaching as they will lay the groundwork necessary to advance research aimed at identifying novel therapeutic strategies to treat neurological diseases derived from in-uterus exposure to specific OP pesticides. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to provide fundamental and timely input for assessment of the human developmental toxicity of malathion and chlorpyrifos and identification of lead compounds for adequate treatment of neurological diseases that result from in-uterus exposure to these pesticides.